Confirming a Participant Truly Understands the Informed Consent Form Before Signing
Authors: Gerald L. Klein, MD1; Melissa Palmer2; Freddy Byrth, BA1; Michael Fath, PhD3
Affiliations: MedSurgPI1; Liver Consulting, LLC2; Cavabio Consulting3
Drug Development
The Point: Consent is meaningful only when participants understand it. Since disclosure does not guarantee comprehension, coordinators must verify both decisional capacity and understanding of the specific study before allowing anyone to sign.
A signature on an informed consent form (ICF) documents that disclosure occurred, but it does not prove the participant understood what they agreed to. It is an important ethical and regulatory obligation in clinical research and simply asking, "Do you have any questions?" is not sufficient to confirm comprehension. International oncology trials repeatedly show that most participants cannot correctly answer basic questions about efficacy, risks, and alternatives even after signing.[1] Determining whether someone truly understands the ICF, and therefore whether they should proceed to enrollment requires two separate checks. First, assess decisional capacity: the ability to understand, appreciate, reason about, and express a choice regarding participation. Second, assess comprehension of the specific protocol. Appropriate education, documentation, and, when needed, Institutional Review Board (IRB) approved procedures for a legally authorized representative or additional capacity assessment should support both steps.
A practical two-step approach lets a coordinator or investigator make this determination in a few minutes. First, screen decisional capacity with the University of California, San Diego (UCSD) Brief Assessment of Capacity to Consent (UBACC), a validated 10-item instrument scored 0 to 2 per item (0 to 20 total) that takes under five minutes to administer and, at a threshold score of 14.5, flags participants who warrant more thorough capacity assessment or remediation before enrollment.[2] To support compliance, sites should document the participant’s teach-back responses, any remediation provided, and the basis for concluding that adequate understanding was achieved; without this documentation, a site may perform the right steps but be unable to demonstrate them during monitoring, inspection, or later dispute. Second, confirm comprehension of the actual study using a short teach-back set such as the nine questions which were developed by Klein et al.[3] These questions address the purpose of the study, potential benefits, side effects, procedures, visit burden, participant responsibilities, payment, cost of care for a study-related injury, effect of nonparticipation on usual care, and any out-of-pocket costs. To apply these questions effectively, ask the participant to respond in their own words rather than yes or no.1 Anyone who cannot answer correctly should be re-educated and re-tested, and only those who then demonstrate understanding should be allowed to sign. Building both steps into the consent workflow, and pilot-testing the ICF and questions on lay readers beforehand, protects vulnerable participants without excluding them.
Time the Nonclinical Program to the Clinical Plan, Not to a Checklist
A common and costly error is treating the nonclinical safety package as a fixed checklist rather than a set of studies timed to specific clinical milestones. ICH M3(R2) ties the required duration of repeat-dose toxicity studies to the intended duration of clinical dosing: first-in-human and short trials are supported by short repeat-dose studies of corresponding length, while clinical dosing of six months or longer generally requires a six-month rodent and a nine-month non-rodent chronic dosing study.[4] Before the first-in-human trial, the nonclinical package must also include the safety pharmacology core battery covering cardiovascular, respiratory, and central nervous system function, with dedicated assessment of ventricular repolarization and QT prolongation.[5] It must also include genotoxicity screening that begins with a gene mutation assay and expands to the full battery before larger or longer trials,[6] plus adequate toxicokinetic and general toxicology data. Reproductive and developmental toxicity and carcinogenicity studies are staged later; they gate specific populations and marketing rather than early trials.
Practical Pointer: at program start, map each nonclinical study to the specific clinical milestone it enables, recognizing that gating requirements vary by intended population, dosing duration, therapeutic area, modality, and regional expectations. This keeps an otherwise clean molecule from stalling simply because a study needed for a particular cohort wasn’t initiated in time.
Devices
Use a Predetermined Change Control Plan to update an AI-enabled device without a new submission
The Point: If your device includes an artificial intelligence-enabled software function that you expect to retrain or refine after authorization, a Predetermined Change Control Plan (PCCP) lets you pre-specify and pre-authorize those changes in your original marketing submission, so you can implement them later without a new 510(k), De Novo, or premarket approval submission.
The FDA’s final guidance issued on 18 August 2025 establishes the framework for PCCPs for AI-enabled device software functions across the 510(k), De Novo, and PMA pathways. The guidance defines three required components: a Description of Modifications that states the changes the manufacturer intends to make, a Modification Protocol that details how each change will be developed, validated, and implemented, and an Impact Assessment that evaluates the effect of the changes on safety and effectiveness. PCCPs are reviewed as part of the marketing submission, and modifications that fall within an approved plan may be implemented without a new submission.[1]
What to do. Keep the plan focused and verifiable, risk-based, evidence-based, transparent, and lifecycle-oriented, in line with the joint FDA, Health Canada, and Medicines and Healthcare products Regulatory Agency guiding principles.[2] Raise the plan early with the review division through a pre-submission, address labeling so users know the device was authorized with such a plan, and do not attempt to include changes to the intended use, which sit outside these plans and still require a new submission. A well-scoped plan converts a series of expensive, sequential submissions into one, and is often the most valuable planning step for a device that will keep learning after it reaches the market.
Practical Pointer: Keep your PCCP narrowly scoped, evidence-based, and transparent, raise it early through a pre-submission, and avoid including intended-use changes, which always require a new submission.
Medical Affairs
Keep the line clear between answering an off-label question and initiating one.
The Point: Medical affairs may respond to an unsolicited request for off-label information, but the rules for firm-initiated scientific exchange are separate and stricter. Treat the two as distinct lanes and never let one drift into the other.
For the reactive lane, the FDA guidance on responding to unsolicited requests remains the reference. Answer only the specific question asked, respond privately to the person who asked rather than broadcasting, keep the information truthful, balanced, non-promotional, and science-based, generate it through medical or scientific personnel, never through the sales force, and document the request and the response.[1]
In the proactive lane, the FDA’s January 2025 final Level 1 guidance on firm‑initiated scientific communications for unapproved uses sets a high bar: source publications must be scientifically sound, required disclosures must accompany the communication, and all materials must remain clearly separated from promotional content, both in substance and in channel, using dedicated webpages, emails, and meeting spaces. In contrast, the reactive lane continues to be governed by the FDA’s 2011 draft guidance on responding to unsolicited requests, which permits manufacturers to provide balanced, non-promotional scientific information when the healthcare professional initiates the inquiry. Distinguishing these two lanes is essential: proactive communications must follow the 2025 framework, while reactive responses must follow the 2011 draft. In practice, this means training medical science liaisons (MSLs) to recognize and preserve an unsolicited request rather than converting it into a proactive pitch, keeping medical information responses balanced and fully referenced, and maintaining the firewall in both content and distribution pathways. The compliance risk rarely lies in possessing off-label science; it lies in blurring who initiated the conversation and where that information is housed.
Practical Pointer: Train MSLs to preserve unsolicited requests exactly as received, keep proactive scientific communications in dedicated non-promotional channels, and document both the request and the response so the lane distinction is always visible.
Publications
Build Good Publication Practice (GPP) 2022 and International Committee of Medical Journal Editors (ICMJE) authorship into the publication plan, not the final draft
Publication integrity failures, guest authorship, ghostwriting, undisclosed conflicts are almost always baked in at the planning stage. Applying GPP and ICMJE authorship criteria early prevents these problems at a fraction of the cost of repairing them later.
When teams establish clear roles, require transparent disclosures, and document decisions rigorously from the outset, they eliminate the conditions that allow integrity issues to take root, One practical safeguard is to require an authorship/contribution table at project kickoff and update it at each draft milestone; GPP 2022 explicitly adopts ICMJE criteria as the default and emphasizes that named authors are accountable for data integrity, so the planning process should make that accountability visible from the start.
MedSurgPI: Elevating Medical and Scientific Communication
MedSurgPI advances the practices described in this paper, clear scientific communication, transparent authorship, disciplined lane management, and responsible innovation. By supporting teams correctly from the start, MedSurgPI helps organizations build credible, compliant, and scientifically sound materials that stand up to scrutiny.
[1] Nusbaum L, Douglas B, Damus K, Paasche-Orlow M, Estrella-Luna N. Communicating Risks and Benefits in Informed Consent for Research: A Qualitative Study. Glob Qual Nurs Res. 2017 Sep 20;4:2333393617732017. doi: 10.1177/2333393617732017. PMID: 28975139; PMCID: PMC5613795
[2] Jeste DV, Palmer BW, Appelbaum PS, Golshan S, Glorioso D, Dunn LB, Kim K, Meeks T, Kraemer HC. A new brief instrument for assessing decisional capacity for clinical research. Arch Gen Psychiatry. 2007;64(8):966-974. doi:10.1001/archpsyc.64.8.966.
[3] Klein G, Morgan R, Zhang, S, et al. Improving Informed Consent Forms (ICFs) in Clinical Trials, Especially for Vulnerable Populations, A Global Need. Presented at: Society of Clinical Research Associates [SOCRA] Annual Conference; September 28-30, 2023; Montreal Canada
[4] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline M3(R2): Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Geneva, Switzerland: ICH; 2009.
[5] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline S7A: Safety Pharmacology Studies for Human Pharmaceuticals. Geneva, Switzerland: ICH; 2000.
[6] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use. Geneva, Switzerland: ICH; 2011.
[7] US Food and Drug Administration. Marketing Submission Recommendations for a Predetermined Change Control Plan for Artificial Intelligence-Enabled Device Software Functions: Guidance for Industry and Food and Drug Administration Staff. Silver Spring, MD: US Food and Drug Administration; December 2024. Accessed July 2, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/marketing-submission-recommendations-predetermined-change-control-plan-artificial-intelligence
[8] US Food and Drug Administration, Health Canada, Medicines and Healthcare products Regulatory Agency. Predetermined Change Control Plans for Machine Learning-Enabled Medical Devices: Guiding Principles. Silver Spring, MD: US Food and Drug Administration; 2025. Accessed July 2, 2026. https://www.fda.gov/medical-devices/software-medical-device-samd/predetermined-change-control-plans-machine-learning-enabled-medical-devices-guiding-principles
[9] US Food and Drug Administration. Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices: Draft Guidance for Industry. Silver Spring, MD: US Food and Drug Administration; December 2011. Accessed July 2, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/responding-unsolicited-requests-label-information-about-prescription-drugs-and-medical-devices